TY - JOUR
T1 - Discovering human diabetes-risk gene function with genetics and physiological assays
AU - Peiris, Heshan
AU - Park, Sangbin
AU - Louis, Shreya
AU - Gu, Xueying
AU - Lam, Jonathan Y.
AU - Asplund, Olof
AU - Ippolito, Gregory C.
AU - Bottino, Rita
AU - Groop, Leif
AU - Tucker, Haley
AU - Kim, Seung K.
N1 - Funding Information:
We gratefully acknowledge organ donors and their families for tissue procurement. We thank Professors Mark McCarthy and Anna Gloyn, and Dr. Anubha Mahajan (University of Oxford) for advice on SNP analysis and data presentation; Drs. Efsun Arda and James Lee for protocols and help with intracellular sorting, and members of the Kim lab and K. Mackenzie for comments on the manuscript. H.P was supported by postdoctoral fellowships from Stanford Child Health Research Institute (UL1 TR001085) and the American Diabetes Association (1–16-PDF-086). Work in H.T’s lab was supported by the National Institute of Health (grant number F32CA110624 and R01CA31534), Cancer Prevention Research Institute of Texas (grant number RP120459) and the Marie Betzner Morrow Centennial Endowment. Work in the Kim lab was supported by the NIH (DK104211, DK107507, DK102612, P30 DK116074 and DK108817), an opportunity pool award through UO1DK105554 (to Dr. J. Florez, Broad Inst.) in the AMP T2D consortium, Juvenile Diabetes Research Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, the H. L. Snyder Medical Foundation, and the Islet Research Core of the Stanford Diabetes Research Center.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Developing systems to identify the cell type-specific functions regulated by genes linked to type 2 diabetes (T2D) risk could transform our understanding of the genetic basis of this disease. However, in vivo systems for efficiently discovering T2D risk gene functions relevant to human cells are currently lacking. Here we describe powerful interdisciplinary approaches combining Drosophila genetics and physiology with human islet biology to address this fundamental gap in diabetes research. We identify Drosophila orthologs of T2D-risk genes that regulate insulin output. With human islets, we perform genetic studies and identify cognate human T2D-risk genes that regulate human beta cell function. Loss of BCL11A, a transcriptional regulator, in primary human islet cells leads to enhanced insulin secretion. Gene expression profiling reveals BCL11A-dependent regulation of multiple genes involved in insulin exocytosis. Thus, genetic and physiological systems described here advance the capacity to identify cell-specific T2D risk gene functions.
AB - Developing systems to identify the cell type-specific functions regulated by genes linked to type 2 diabetes (T2D) risk could transform our understanding of the genetic basis of this disease. However, in vivo systems for efficiently discovering T2D risk gene functions relevant to human cells are currently lacking. Here we describe powerful interdisciplinary approaches combining Drosophila genetics and physiology with human islet biology to address this fundamental gap in diabetes research. We identify Drosophila orthologs of T2D-risk genes that regulate insulin output. With human islets, we perform genetic studies and identify cognate human T2D-risk genes that regulate human beta cell function. Loss of BCL11A, a transcriptional regulator, in primary human islet cells leads to enhanced insulin secretion. Gene expression profiling reveals BCL11A-dependent regulation of multiple genes involved in insulin exocytosis. Thus, genetic and physiological systems described here advance the capacity to identify cell-specific T2D risk gene functions.
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U2 - 10.1038/s41467-018-06249-3
DO - 10.1038/s41467-018-06249-3
M3 - Article
C2 - 30242153
AN - SCOPUS:85053726357
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3855
ER -